It has been disclosed, for example, in U.S. Pat. No. 3,362,956 that certain indazole derivatives are possessed of central nervous actions such as antianxietic activity, antiepileptic activity and the like. Also, there is a description in Arzneim.-Forsch., 37(4), 498-502 (1987), stating that certain piperazine derivatives have a function to inhibit calmodulin.
The compound represented by the formula (1) is a novel compound, and its salts and hydrates are also novel compounds. It was revealed that this compound represented by the formula (1) and its salts can show strong calmodulin inhibition action and also show excellent brain protecting action in various cerebral disorder animal models. In consequence, this compound is expected as a drug for use in the prevention and treatment of various diseases caused by the excess activation of calmodulin and cerebral disorders caused by ischemic brain disease, brain degenerative disease, traumatic brain disease, drug intoxication, hypoxia and the like.
Hydrochloride anhydrate of the compound of formula (1) can be prepared by carrying out crystal precipitation treatment of the free base from a mixture of an organic solvent and hydrochloric acid. However, it was found that crystals of the anhydrate obtained in this manner contain the organic solvent used for the crystal precipitation, and the solvent contained in the crystals cannot easily be removed even by heat drying under a reduced pressure. For example, when ethanol was used, the amount of ethanol contained in the crystals was a large and broad value of from 18,000 to 33,000 ppm. It was revealed also that prediction of the amount of solvent contained in the crystals and its regulation to a predetermined level cannot be made easily.
On the other hand, when methanol was used as the solvent at the time of crystal precipitation, the thus obtained hydrochloride anhydrate of the compound of formula (1) also contained methanol, but it was able to remove the contained methanol almost completely when the crystals were dried with heating (120.degree. C.) under a reduced pressure for several days or more. However, the hydrochloride anhydrate obtained by removing methanol in this way showed a property to absorb moisture in response to the environmental humidity at room temperature (showed a property to absorb moisture when the humidity is high but release moisture when humidity is low, see FIG. 1).
Thus, it was revealed that crystals of the hydrochloride anhydrate of the compound of formula (1) cannot easily be made into pharmaceutical preparations, because they cause various problems, so that they are not appropriate as a pharmaceutical material.